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Toxicological information

Carcinogenicity

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Administrative data

Description of key information

No evidence of carcinogenicity was seen in rats after exposure to approximately 1000 mg/kg bw of phthalic anhydride or in male and female mice after exposure to 4670 and 3430 mg/kg bw, respectively, in comprehensive chronic (105-week) feeding study ( Huff, 1984; Kluwe, 1986; NCI, 1979).

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records
Reference
Endpoint:
carcinogenicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Well documented study from the NCI (National Cancer Institute).
Reason / purpose for cross-reference:
reference to same study
Principles of method if other than guideline:
Method: other: see freetext ME
Groups of 50 rats of each sex were administered phthalic anhydride at one of 2 doses, either 7.500 or 15.000 ppm (ca. 500, 1000 mg/kg bw/d) for 105 weeks. Matched controls consisted of 20 untreated rats of each sex. All surviving rats were killed at the end of the period of administration of the test chemical. All animals were checked twice daily for deaths. Observations for sick, tumor-bearing, and moribund animals were recorded daily. clinical examination and palpation for masses were performed each month, and the animals were weighed at least once per month. the pathologic evaluation consisted of gross and microscopic examination of major tissues, major organs, and all gross lesions.
GLP compliance:
not specified
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Route of administration:
oral: feed
Vehicle:
other: diet
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
105 w
Frequency of treatment:
daily
Post exposure period:
none
Remarks:
Doses / Concentrations:
7500, 15000 ppm = ca. 500, 1000 mg/kg bw/d
Basis:

No. of animals per sex per dose:
50 animals
Control animals:
yes, concurrent no treatment
Details on study design:
Post-exposure period: no
Details on results:
Result (carcinogenicity): negative
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Sex:
male/female
Remarks on result:
other: Effect type: carcinogenicity
RS-Freetext:
F344 rats (50/sex/group) were fed diets contenting 7500 or 15,000 ppm phthalic anhydride for 105 weeks (approx. 500 and 1,000 mg/kg bw/day). The observation that the test compound is unstable (2.59% loss of activity per day at room temperature) has to be noted, although this is of minor relevance because the diet was prepared fresh every 1 to 1-1/2 weeks and the diet was stored at 5 degree Celsius, consequently the hydrolysis is assumed to be lower than 26%.

Survival and non-carcinogenic effects see robust summary chapter repeated dose toxicity.

Animal disposition summary
Control low-dose high dose
Animals initial in study: males (females)
20(20) 50(50) 50(50)
Natural death 3(2) 4(6) 9(2)
Moribund sacrifice
3(1) 2(2) 5(7)
Terminal sacrifice 14(17) 44(42) 36(41)

Tumor summary:
Total animals with primary tumors
19(13) 47(37) 46(36)
Total primary tumors
37(18) 101(58) 84(53)
Total animals with benign tumors
18(12) 45(27) 43(32)
Total benign tumors
28(15) 77(38) 63(44)
Total animals with malignant tumors
7(3) 20(16) 21(8)
Total malignant tumors
7(3) 24(20) 21(9)

Total animals with secondary tumors
0(0) 0(1) 3(1)
Total secondary tumors
0(0) 0(1) 3(1)
Total animals with tumors uncertain
benign or malignant
2(0) 0(0) 0(0)
Total uncertain tumors
2(0) 0(0) 0(0)
Total animals with tumors uncertain
primary or metastatic
0(0) 0(0) 0(0)
Total uncertain tumors
0(0) 0(0) 0(0)

PATHOLOGICAL EXAMINATION:
By inspection, there appeared to be no difference between the dosed and control groups in frequency or distribution of neoplasms, except for malignant lymphoma in the female rats. The incidence of malignant lymphoma in the control females was 1/20 (5%) in low-dose females, 11/50 (22%), and in high-dose females, 4/50 (8%). Due to the high and fluctuating incidence of this type of malignant lymphoma in control F344 rats, the apparent differences incidences of the tumor in the dosed and control groups were not considered to be compound related. Statistical analysis revealed that a departure from linear trend (P = 0.019) is found in the incidence of lymphoma in female rats, due to the relatively large proportion of 11/50 (22%) in the low-dose group compared with 4/50 (8%) in the high-dose group and 1/20 (5%) in the control group. The results of the Fisher exact test are not significant.
Current historical records at this laboratory indicate an incidence of lymphoma in female rats of 14/285 (4.9%), and, although the majority of the control groups had incidences of less than 5%, one control group was observed to have an incidence as high as 4/20 (20%). Since the results of the Fisher exact test were not significant and since the historical data concerning lymphoma indicates the possibility of an occasional high spontaneous rate of lymphoma, the evidence of association of the lymphomas in the dosed group of female rats with the chemical is questionable.

Further statistical analysis:
In female rats, the result of the Cochran-Armi tage test positive dose-related trend in the incidence of alveolar/ bronchiolar adenomas is significant (P = 0.020), but the results of the Fisher exact test are not significant. The results of the statistical tests on the incidences of alveolar/bronchiolar carcinomas and of alveolar/bronchiolar adenomas or carcinomas are not significant. In male rats, the results of the statistical tests on the incidences of lung tumors are not significant.

A significant dose-related trend (P = 0.037) in the negative direction is observed in the incidence of pheochromocytomas of the adrenal in male rats.

Incidence of primary tumors (%) in selected tissues:

Organ control low-dose high-dose

Male rats

Lung: Alveolar/Bronchiolar Adenoma
1/20 (5%) 4/50 (8%) 1/50 (2%)
Hematopoietic System: Lymphomas
4/20 (20%) 11/50 (22%) 12/50 (24%)
Hematopoietic System: Lymphomas or Leukemias
5/20 (25%) 12/50 (24%) 15/50 (30%) Adrenal: Pheochromocytoma
6/20 (30%) 8/48 (17%) 5/49 (10%)

Female rats

Lung: Alveolar/Bronchiolar Adenoma 0/20 (0%) 0/50 (0%) 5/50 (10%)
Carcinoma 1/20 (5%) 3/50 (6%) 1/50 (2%)
Carcinoma or Adenoma
1/20 (5%) 3/50 (6%) 6/50 (12%)
Hematopoietic System: Lymphomas
1/20 (5%) 11/50 (22%) 4/50 (8%)
Adrenal: Pheochromocytoma
0/20 (0%) 0/49 (0%) 3/49 (6%)

Severe chronic inflammatory, degenerative, or proliferative lesions frequently seen in aged rats occurred with approximately equal frequency and severity in the dosed and control groups of animals.

Conclusion: No tumors occurred in the rats of either sex at incidences that could be clearly related to the administration of the test compound. It is concluded that under the conditions of this bioassay, phthalic anhydride was not carcinogenic for F344 rats of either sex.
Executive summary:

Groups of 50 rats of each sex were administered phthalic anhydride at one of 2 doses, either 7.500 or 15.000 ppm (ca. 500, 1000 mg/kg bw/d) for 105 weeks. Matched controls consisted of 20 untreated rats of each sex. All surviving rats were killed at the end of the period of administration of the test chemical. All animals were checked twice daily for deaths. Observations for sick, tumor-bearing, and moribund animals were recorded daily. clinical examination and palpation for massess were performed each month, and the animals were weighed at least once per month. the pathologic evaluation consisted of gross and microscopic examination of major tissues, major organs, and all gross lesions.

The NOAEL = 1000 mg/kg bw/d for cancerogenicity (rat, m+f)

No tumors occurred in the rats of either sex at incidences that could be clearly related to the administration of the test compound.  It is concluded thatunder the conditions of this bioassay, phthalic  anhydride was not carcinogenic for F344 rats of either sex.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Species:
rat
Quality of whole database:
Well documented study from the NCI (National Cancer Institute).

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Based on the available studies a non-classification for carcinogenicity is justified.

Additional information

There are no data available for PA. Due to the rapid hydrolysis of pthalic anhydride to PA a read across with phthalic acid is performed.

Carcinogenicity studies have been conducted with phthalic anhydride in rats and mice. Groups of 20 control and 50 treated Fischer 344 rats per sex were exposed via the diet at levels of 0, 7500, or 15,000 ppm (0, approx. 500 or 1000 mg/kg bw/day) for 105 weeks. The survival rate at the end of the treatment period was at least 70 % in all groups. There were no significant non-neoplastic abnormalities, and adverse effects were limited to decreased body-weight gain at dose levels of 1000 mg/kg bw/day. No difference was observed between the dosed and control groups in frequency or distribution of neoplasms, except for malignant lymphoma in the female rats. The incidence of malignant lymphoma in the control females was 1/20, in the low-dose females 11/50, and in the high dose females 4/50. Due to the high and fluctuating incidence of this type of malignant lymphoma commonly observed in control F344 rats, the apparent difference in incidences of the tumor in the dosed and control groups were not considered to be compound related (NCI, 1979).

For the mice (B6C3F strain), groups of identical size were exposed via the diet at level of 0, 25,000, or 50,000 ppm for the first 32 weeks of a 104 weeks treatment period. Because of excessive bodyweight loss the exposure levels in males were reduced to 12,500 or 25,000 ppm, respectively, and the doses for the females were reduced to 6250 and 12,500 ppm, respectively, for the remainder of the study. Nonneoplastic effects observed at all doses included increased incidences of lung and kidney lymphocytosis, adrenal atrophy and mineralization of the thalamus. There was no difference in mortality among the groups, and the survival rates at the end of the treatment period were at least 70 % in all groups. No neoplastic changes that were considered to be treatment-related were observed in the mice (NCI, 1979).

Therefore no evidence of carcinogenicity was seen in rats or mice.